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Movement is controlled by neuronal central pattern generator (CPG) networks that are segmentally organised in organisms across the animal kingdom. The precise role of neuromodulators in the function, development and, particularly, the maintenance of these circuits is currently unresolved. This study investigates the effects of chronically altered signalling of tyramine and/or octopamine, two well established neuromodulators, in Drosophila larval locomotion. It shows that tyramine reduces crawling speed in larvae, whereas octopamine increases speed up to a physiological maximum. Changes in crawling speed are mediated by modulating stride duration, whilst stride length remains constant. These two neuromodulators also affect segmental muscle contraction and relaxation rates, indicative that the effects on crawling speed are likely to be at least partially due to modulatory effects on muscle physiology. Muscle recordings from muscle M6 in two adjacent segments, during fictive forward locomotion show that stride duration is influenced by a variable time delay between segmental CPG outputs. Frequency and duration of individual segmental outputs, by contrast, remains constant. The behavioural and electrophysiological data suggest, therefore, that the segmental locomotor CPG outputs remain constant in response to chronically altered neuromodulatory signalling. This study also identified a close spatial proximity of motor neuronal dendritic branches and putatively octopaminergic and/or tyraminergic synaptic terminal varicosities in the ventral nerve cord (VNC) neuropil. Moreover, manipulation of a putatively octopaminergic and/or tyraminergic subpopulation of interneurons, located in anterior brain regions, is sufficient to induce a similar, albeit smaller, larval crawling deficit. This indicates that the effects of locomotion may be induced in the central nervous system. This is confirmed in identified motor neurons as chronic changes in octopaminergic and/or tyraminergic signalling increase the frequency of bursting of action potential firing. In addition, the synaptic current amplitudes are substantially reduced in both ventral and dorsal muscle- innervating motor neurons, indicative of an effect to presynaptic excitation. In contrast, the function of neuromuscular junction remains largely unchanged. Taken together, this data shows that neuromodulation is sufficient to alter the output of a relatively small group of neurons, that comprise the locomotor CPG. The site of action of these modulators is, however, likely to be diverse.

Background: Tendinosis is a painful chronic, degenerative condition characterized by objective changes in the tissue structure of a tendon. Hallmark features in tendinosis tendons include increased number of cells (hypercellularity), extracellular matrix (ECM) degradation and disorganized collagen. The progression of these pathological changes seen in tendinosis is neither well characterized nor fully understood. Studies have suggested that there are biochemical and mechanical elements involved in tendinosis. From a biochemical perspective, studies have shown that the tendon cells, tenocytes, produce a number of neuronal signal substances/neuromodulators, such as substance P (SP) and acetylcholine (ACh), traditionally thought to be confined to the nervous system. Furthermore, it has been shown that the expression of these neuromodulators is elevated in tendinosis tendons as compared to normal healthy tendons. Interestingly, studies on other tissue types have revealed that both SP and ACh can induce tissue changes seen in tendinosis, such as hypercellularity and collagen disorganization. From a mechanical angle, it has been suggested that overload of tendons, including extensive strain on the primary tendon cells (tenocytes), causes the degenerative processes associated with tendinosis. In vivo studies have shown that in overloaded tendons, the presence of neuromodulators is elevated, not least SP, which also precedes the development of the tissue changes seen in tendinosis. This further supports the importance of combining biochemical factors and mechanical factors in the pathogenesis of tendinosis. Hypotheses: In this thesis project, we hypothesize: 1) that neuromodulators, such as SP and ACh when stimulating their preferred receptors, the neurokinin 1 (NK-1 R) and muscarinic receptors (mAChRs), respectively, can cause increased tenocyte proliferation; 2) that the effects of SP and ACh on tenocyte proliferation converge mechanistically via a shared signalling pathway; 3) that mechanical loading of tenocytes results in increased production of SP by the tenocytes; and 4) that SP enhances collagen remodelling by tenocytes via NK-1 R. Model system: In vitro studies offer insight into the function of healthy tendon matrix and the etiology of tendinopathy. Using a cell culture model of human primary tendon cells, highly controlled experiments were performed in this thesis project to study a subset of biological and mechanical parameters that are implicated in tendinosis. The FlexCell® Tension System was used to study the influence of mechanical loading on tenocytes. As well, a collagen gel contraction assay was used to examine the intrinsic ability of tenocytes to reorganise type I collagen matrices under the influence of the neuromodulator SP. Results: The studies showed that exogenous administration of SP and ACh results in increased tenocyte proliferation that is mediated via activation of the ERK1/2 mitogenic pathway when the preferred receptors of SP and ACh, the NK-1 R and mAChRs, respectively, are stimulated. Furthermore, the studies resulted in the novel finding that SP and ACh both converge mechanistically via transforming growth factor (TGF)-β1 and that a negative feedback mechanism is present in which TGF-β1 downregulates the expression of mAChRs and NK-1 R. The studies also showed that SP can increase collagen remodelling and upregulate expression of genes related to tendinosis. Finally, it was established that tenocytes are mechanoresponsive by showing that cyclic mechanical loading increases the expression of SP by human tenocytes. Conclusions: This thesis work concludes that stimulation of NK-1 R and mAChRs results in proliferation of human tenocytes, which both involve the ERK1/2 signalling pathway. It also shows that SP and ACh converge mechanistically via TGF-β1 in their contribution to tenocyte proliferation. The role of hypercellularity in tendinosis tissue is unknown. Possibly, it has different roles at different stages of the disease. The findings also show that SP increases collagen remodelling, suggesting that increased SP not only results in hypercellularity but also contributes to the collagen morphology in tendinosis.

Le comportement normal d’un individu est le résultat de l’interaction entre les neurones, appelée la corrélation du bruit, qui se déroule en intra et inter les régions cérébrales. Cette corrélation joue un rôle important dans l’attention, la mémoire, la perception et la prise de décision. Plusieurs études ont montré qu’il y a une diminution de la corrélation du bruit pendant les processus d’apprentissage et que son augmentation est corrélée avec les échecs comportementaux. De ce fait, comprendre comment cette corrélation est ajustée en fonction des changements du comportement est très important pour déterminer les processus neuronaux sous-jacents. En effet, ces processus neuronaux sont contrôlés par les neuromodulateurs. Plusieurs maladies neuropsychiatriques sont liées à une anomalie de régulation des ces neuromodulateurs. Par exemple, les personnes qui soufrent d’un trouve de déficit de l’attention avec hyperactivité (TDAH) ont un déficit attentionnel qui très handicapant de la vie quotidienne. En effet, déficit attentionnel est atténué par une augmentation sélective de la neuromodulation noradrégergique. Cependant les mécanismes d’action des molécules utilisées, comme la Ritaline qui est un agoniste noradrénergique, sont inconnus. L’objectif de ma thèse est d’étudier et comprendre les processus neuronaux liés à cette maladie ainsi que les mécanismes d’action des agonistes noradrénergiques. Plus précisément, j’ai étudié comment cette corrélation du bruit est ajustée en fonction des changements de l’engagement attentionnel chez des sujets sains et des sujets avec un déficit attentionnel. Afin de réaliser mes travaux de recherche j’ai utilisé la technique d’enregistrement élecrtophysiologiques chez le primate non-humain combiné avec des injections pharmacologiques. Mes travaux de recherche ont montrés que cette corrélation du bruit diminue quand l’engagement attentionnel augmente. De plus, cette corrélation du bruit change d’une manière rythmique dans le temps afin de s’adapter aux changements comportementaux. Spécifiquement, on montre que la modulation noradrénergique a des effets locaux en diminuant la corrélation du bruit au sein des réseaux neuronaux / Optimal behavior is the result of interactions between neurons, called noise correlation, both within and across brain areas. Noise correlations play an important role in attention, memory, perception and decision-making. Many studies have shown that noise correlations decrease in the process of learning and to correlate with overt behavioral performance, higher noise correlations predicting behavioral failures. Identifying how these neuronal interactions adjust to the ongoing behavioral demand is key to understand the neuronal processes and computations underlying optimal behavior. These neuronal processes depend on tightly controlled activity in brainstem neurons that release neuromodulators at their target sites. Understanding the link between neuromodulation and the variation of noise correlation within brain region would help to describe mechanisms by which neuromodulator exerts its effect. My thesis aims to investigate how noise correlations is adjusted to cognitive and task engagement both in healthy brain state and in brain suffer from attention deficit. To do so, I combined pharmacology, behavioral and electrophysiology in non-human primate. Overall, we show that noise correlations decrease across tasks as cognitive engagement and task demands increase. Specifically, noradrenergic modulation induce a local effect by decreasing noise correlations within networks

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Intraspecific aggression is a widely distributed, highly plastic behaviour throughout the animal kingdom and serves to secure resources, as members of the same species compete for identical ecological niches. But the costs can rapidly exceed the advantages. Over the past years, the two-spotted Mediterranean field cricket, Gryllus bimaculatus, has emerged to a model organism for studying the mechanisms underlying aggressive behaviour. Crickets implement seemingly complex decisions via the action of well-known neuromodulators with analogues in vertebrates including humans. This study shows that an individual´s decision to approach or avoid an agonistic stimulus is mainly shaped by social experiences gathered during nymphal development and early adult life. In particular, the chronic subjugation of nymphs by adult males in the breeding colony and the absence thereof lead to the establishment of distinct behavioural ethotypes shifting the answer to the question of whether inter-individual differences are nature or nurture in favour of nurture. Individuality in adult behaviour can thus result from social experiences during development alone. Moreover, the decision to approach or avoid a potentially agonistic stimulus is differentially modulated by the actions of the neuromodulators octopamine, serotonin and nitric oxide, which are released in response to social interactions. Interestingly, the social status dependent predisposed response to an antennal stimulus can be altered by octopamine alone. Furthermore, the present study reveals that the nitridergic and serotonergic system play a major role in the assessment of agonistic signals.:1 Introduction ...................................................................................................... 1 2 Methods ............................................................................................................ 6 2.1 Experimental animals .................................................................................... 6 2.2 Experimental groups based on social experiences and isolation time .................................................................................. 8 2.3 Evaluation of dominance and subordination ......................................... 10 2.4 Multiple wins and defeats ...................................................................... 12 2.5 Contests against a hyper-aggressive opponent .................................... 13 2.6 The mandible threat display in response to antennal stimulation and feeding ............................................................................. 13 2.7 The priming effect .................................................................................... 14 2.8 Influence of food as a resource ............................................................... 14 2.9 Set up and video tracking ....................................................................... 15 2.10 Evaluation of exploratory behaviour ..................................................... 16 2.11 Response to a single antennal touch with an adult male´s antenna ..................................................................................................... 17 2.12 Pharmacological treatment ...................................................................... 18 2.13 Data analysis ............................................................................................. 20 3 Results ............................................................................................................ 22 3.1 Responses of nymphs and adults towards conspecifics ........................... 22 3.2 Mandible threat display and the mandible spread angle .......................... 24 3.3 Influence of dominance and subordination ................................................. 26 3.4 Influence of prior antennal stimulation (priming) .......................................... 28 3.5 Influence of priming coupled with CDM ...................................................... 30 3.6 Influence of food as a resource .................................................................... 30 3.7 Effects of different social experiences during nymphal development on adult behaviour ................................................................. 31 3.8 Turning responses as a reaction to a single antennal touch with an adult male´s antenna ....................................................................... 34 3.8.1 Short term isolates ............................................................................... 34 3.8.2 Long term isolates ............................................................................... 38 3.9 Effects of neuromodulatory drugs on behavioural elements in STI and LTI crickets ............................................................... 43 3.9.1 Aggression ............................................................................................ 43 3.9.2 General motility .................................................................................... 46 3.9.3 Turning responses ................................................................................. 50 3.9.3.1 Influence of octopaminergic drugs .................................... 50 3.9.3.2 Influence of nitridergic drugs ............................................... 53 3.9.3.3 Influence of serotonergic drugs .......................................... 58 4 Discussion .................................................................................................... 68 4.1 Nymphal interactions and their consequences for adult behaviour .......... 68 4.2 The decision to approach or avoid an agonistic stimulus ........................... 72 4.3 The role of neuromodulators released in response to social experience .... 77 4.4 Overall conclusion and outlook .................................................................... 84 5 Summary .......................................................................................................... 86 6 Zusammenfassung ........................................................................................... 91 7 References ........................................................................................................ 98 8 Appendix .......................................................................................................... 109 8.1 Figures and Tables .......................................................................................... 109 8.2 Publications and published abstracts ............................................................ 111 8.3 Curriculum vitae ............................................................................................ 113 8.4 Acknowledgments ......................................................................................... 115

<p>This work studies the effect of dopamine (DA) and adenosine triphosphate (ATP) on lipid membranes using a number of complementary experimental methods. These methods include Dynamic Light Scattering to measure electrostatic surface potentials, solid-state Nuclear Magnetic Resonance to measure the degree of lipid acyl chain order, Electron Paramagnetic Resonance to measure changes in membrane viscosity, and X-ray diffuse scattering to measure structural and material parameters of lipid bilayers. It is shown that both DA and ATP have a measurable affinity to the lipid-water interface even in the absence of specialized biological receptors. These results are important for understanding the function of DA and ATP in cellular processes.</p>

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